Better understanding of host response to in vivo challenge with HIV may assist the design and evaluation of HIV vaccines. Given uncertainties about host and viral genetic variation across populations, it is important that studies be conducted in the sub-Saharan African populations in which the need for an HIV vaccine is most urgent. This study aims to investigate immunogenetic and virologic factors associated with protection from HIV in the context of perinatal HIV exposure. We plan to recruit a cohort of infants born to HIV-infected mothers in South Africa who have received no antiretroviral drugs before delivery in order to study the development of anti-HIV responses before they may be affected by antiretroviral drugs. These HIV-infected mothers will be identified post-partum and will be offered post-exposure prophylaxis for their infants. Infants will be followed-up to ascertain their infection status. First, the nature of anti-HIV responses in cord blood of infants who escape HIV infection will be investigated using new methods of quantifying antigen-specific intracellular cytokine production by CD4+ and CD8+ T-cells by flow cytometry. Second, attention is focused on interactions between major histocompatibility genes between mother and child, and on the immunologic relevance of these genetic relationships for the development of allogenic and anti-HIV responses which may convey some protection against HIV transmission. Following the hypothesis that fetal contact with foreign maternal histocompatibility antigens in utero may, under certain conditions, help to prevent infection, we plan to measure fetal cord blood lymphocyte reactivity to stimulation with maternal cells, human leukocyte antigen (HLA) genotypes of mother and child, and B-chemokine production and to compare these factors between infected and uninfected infants, and between those with and without anti-HIV responses. We will also investigate whether mutation in maternal virus populations accounts for failure to detect anti-HIV responses in the infant. Since mothers and infants are genetically-related, rare for other routes of HIV transmission, and pregnancy is a unique immunologic circumstance with known trafficking of cells in both directions across the placenta (mother to child, child to mother), maternal-infant HIV transmission offers a distinctive lens through which to attempt to better understand the complexities of potentially protective host immunologic response to HIV.